1. IKKa is required for maintaining skin homeostasis and preventing skin tumorigenesis. However, its signaling has not been extensively investigated. In the present study, we generated two mouse lines that expressed different levels of transgenic IKKa in the basal epidermis under the control of the keratin 5 promoter and further evaluated their effects on the major pathways of inflammation, proliferation, and differentiation in the skin. Regardless of the transgenic IKKa levels, the mice develop normally. Because IKKa deletion in keratinocytes blocks terminal differentiation and induces epidermal hyperplasia and skin inflammation, we depleted the endogenous IKKa in these transgenic mice and found that the transgenic IKKa represses epidermal thickness and induces terminal differentiation in a dose-dependent manner. Also, transgenic IKKa was found to elevate expression of Max dimer protein 1 (Mad1) and Ovol1, c-Myc antagonists, but repress activities of EGFR, ERK, Jun-amino-terminal kinases, c-Jun, Stat3, and growth factor levels in a dose-dependent fashion in the skin. Moreover, EGFR reduction represses IKKa deletion-induced excessive ERK, Stat3 and c-Jun activities and skin inflammation. These new findings indicate that elevated IKKa expression not only represses epidermal thickness and induces terminal differentiation, but also suppresses skin inflammation by an integrated loop. Thus, IKKa maintains skin homeostasis through a broad range of signaling pathways. 2. IKKa in lung cancer development. IKKa downregulation has been reported in human squamous cell carcinomas (SCCs) of the skin, lungs, and other organs. Although we have previously demonstrated that IKKa deficiency promotes or induces skin SCCs in mice, we did not have evidence for the role of IKKa in lung SCCs in mice. Our recent results showed that approximately 30% of Ikka-KA/KA mice expressing a kinase-dead and reduced IKKa develop lung SCCs. Because most Ikka-KA/KA mice develop severe skin lesions (wounds and inflammation) and some develop skin tumors, these mice start to die after 6 months of age. To reduce the skin phenotypes in the mice, we introduced two types of transgenic IKKa into the epidermis of Ikka-KA/KA mice. After the Lori.IKKa transgene, which is only expressed in the epidermis, was introduced into Ikka-KA/KA mice, the skin conditions were greatly improved and Ikka-KA/KA/Lori.IKKa mice were able to live longer. Almost all the Ikka-KA/KA/Lori.IKKa mice develop lethal SCCs. Because SCCs are derived from lung epithelial cells expressing keratin 5 (K5), we then introduced the K5.IKKa gene into the skin and lungs in Ikka-KA/KA mice. Most Ikka-KA/KA/K5.IKKa mice can even live much longer than Ikka-KA/KA/Lori.IKKa mice. No SCCs have been found in Ikka-KA/KA/K5.IKKa mice but a few (&lt;10%) of the mice developed alveolar carcinomas. These preliminary results indicate that IKKa deficiency is involved in lung SCC development and that IKKa is capable of preventing SCC development in lung epithelial cells.